Tumor suppressor gene inactivation during cadmium-induced malignant transformation of human prostate cells correlates with overexpression of de novo DNA methyltransferase.
Tumor suppressor gene inactivation during cadmium-induced malignant transformation of human prostate cells correlates with overexpression of de novo DNA methyltransferase.
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DOI：
10.1289/ehp.10207
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发表时间：
2007-10
影响因子：
10.4
通讯作者：
Waalkes MP
中科院分区：
文献类型：
--
作者：
Benbrahim-Tallaa L;Waterland RA;Dill AL;Webber MM;Waalkes MP
DNA甲基化异常在肿瘤发生中很常见。典型的模式似乎涉及维持DNA甲基转移酶DNMT 1的表达减少，诱导基因组低甲基化，而从头DNMT 3a或3b的表达增加导致基因特异性高甲基化。在镉诱导的恶性转化过程中，发生了一种不寻常的基因组高甲基化模式，我们研究了这种模式，以深入了解特定DNMT在肿瘤发生中的作用。基因表达和DNA甲基化进行了评估，在控制和慢性镉转化的前列腺上皮细胞（CTPE）使用逆转录聚合酶链反应（RT-PCR），蛋白质印迹分析，甲基化特异性PCR，甲基接受试验。在10周的镉暴露，诱导恶性转化，逐步增加广义DNMT酶活性发生与DNMT 3b的过度表达DNMT 1的表达没有变化。DNMT 3b表达增加先于DNMT酶活性增加。普鲁卡因酰胺，一种特异性DNMT 1抑制剂，逆转镉诱导的基因组DNA超甲基化。肿瘤抑制基因RASSF 1A和p16的表达减少，大约在DNMT 3b过度表达首次发生时开始，此后逐渐减少。RASSF 1A和p16启动子区域在CTPE细胞中高度甲基化，表明通过超甲基化沉默，而DNA去甲基化剂5-氮杂-2 ′-脱氧胞苷逆转了这种沉默。DNMT 1抑制仅适度增加CTPE细胞中RASSF 1A和p16的表达，并且没有完全逆转沉默。这些数据表明，DNMT 3b过表达可导致广泛的DNA超甲基化和基因沉默，但DNMT 1是维持这些作用所必需的。基因组DNA超甲基化模式与DNMT 3b上调一起可能提供一组独特的生物标志物，以特异性地识别镉诱导的人类前列腺癌。
Aberrant DNA methylation is common in carcinogenesis. The typical pattern appears to involve reduced expression of maintenance DNA methyltransferase, DNMT1, inducing genomic hypomethylation, whereas increased expression of de novo DNMT3a or 3b causes gene-specific hypermethylation. During cadmium-induced malignant transformation, an unusual pattern of genomic hypermethylation occurred that we studied to provide insight into the roles of specific DNMTs in oncogenesis. Gene expression and DNA methylation were assessed in control and chronic cadmium-transformed prostate epithelial cells (CTPE) using reverse transcription–polymerase chain reaction (RT-PCR), Western blot analysis, methylation-specific PCR, and methyl acceptance assay. During the 10-weeks of cadmium exposure that induced malignant transformation, progressive increases in generalized DNMT enzymatic activity occurred that were associated with over-expression of DNMT3b without changes in DNMT1 expression. Increased DNMT3b expression preceded increased DNMT enzymatic activity. Procainamide, a specific DNMT1 inhibitor, reversed cadmium-induced genomic DNA hypermethylation. Reduced expression of the tumor suppressor genes, RASSF1A and p16, began about the time DNMT3b overexpression first occurred and progressively decreased thereafter. RASSF1A and p16 promoter regions were heavily methylated in CTPE cells, indicating silencing by hypermethylation, while the DNA demethylating agent, 5-aza-2′-deoxycytidine, reversed this silencing. DNMT1 inhibition only modestly increased RASSF1A and p16 expression in CTPE cells and did not completely reverse silencing. These data indicate that DNMT3b overexpression can result in generalized DNA hypermethylation and gene silencing but that DNMT1 is required to maintain these effects. The pattern of genomic DNA hypermethylation together with up-regulation of DNMT3b may provide a unique set of biomarkers to specifically identify cadmium-induced human prostate cancers.
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DOI：
10.1073/pnas.93.18.9821
发表时间：
1996-09-03
影响因子：
11.1
作者：
Herman, JG;Graff, JR;Baylin, SB
通讯作者：
Baylin, SB
影响因子：
64.5
作者：
Okano, M;Bell, DW;Li, E
通讯作者：
Li, E
DOI：
10.1159/000015331
发表时间：
1999-01-01
期刊：
CYTOGENETICS AND CELL GENETICS
影响因子：
--
作者：
Okano, M;Takebayashi, S;Li, E
通讯作者：
Li, E
DOI：
10.1006/bbrc.1993.1750
发表时间：
1993-06-30
影响因子：
3.1
作者：
BALAGHI, M;WAGNER, C
通讯作者：
WAGNER, C
影响因子：
4.7
作者：
Jin, F;Dowdy, SC;Jiang, SN
通讯作者：
Jiang, SN